I am skeptical about bumetanide treatment of autism

Let me first disclaim that, while I can publish enough scientific articles to match my job description, I do not consider myself really worth the honorary qualification of a "scientist". Nevertheless, I often use the opportunity to give my twopence on scientific subjects and on the use of science to make life better.

In the December 2012 issue of Translational Psychiatry, E. Lemonnier et al. published an article titled A randomised controlled trial of bumetanide in the treatment of autism in children. The team claims to have tested the diuretic bumetanide by a double-blind, placebo-controlled clinical trial on a group of 60 autistic children aged 3-11 and to have achieved significant improvements. The presumed mechanism of action involves GABA-ergic neurons.

My intuition says simple stuff given orally is, to say the least, highly unlikely to bring improvement in autism spectrum disorders or other conditions based on fundamentally different wiring of the nervous system. Any study reporting such improvement immediately switches my alarms on. And when I read the actual report, I typically find more alarm-switchers.

In previous years, I have written two posts on what I consider quackery concerning another condition - attention deficit and hyperactivity disorder (ADHD). My 2008 post I am skeptical about food additives - hyperactivity link featured the theories that ADHD was caused by "food additives" (?!) or TV watching. My 2011 post ADHD quackery in scientific journal, again addressed the idea to treat ADHD with restricted elimination diets. The stidies I criticized in these posts, similarly to the bumetanide treatment mentioned above, were all published in respected peer-reviewed scientific journals. Unfortunately, this doesn't automatically guarantee good science, let alone good ethics.

Let me cite these older texts. From the 2008 post: "Why didn't anybody try to conduct a study on animal models? At least, I cannot find such an article in PubMed. Animal studies are generally more standardized and hence more reliable than human ones. I know that in many countries it is easier to obtain a permit to experiment on humans than on animals, but still, why not get to the work seriously and do first the paperwork required and then the animal study itself? Why was the study done only on children, after hyperactivity problems, when present, are thought to persist for life? Is it because adults are generally happy with their own flawed selves but demand perfection from their children, relentlessly drawing the little ones to some superhuman standards of intelligence and behaviour?"

From the 2011 post: "People of science have a saying that extraordinary claims require extraordinary evidence. Any claims for successful treatment of a socially important condition are extraordinary... I would ask again, as I did in my old post, why wasn't the study done first on animal models? And if someone thinks animal models of ADHD are not satisfactory (i.e. fail to produce the crazy results wanted and expected by the researcher), why wasn't the experiment done first on adult volunteers with ADHD? Maybe because no adult, except some patients with much more severe diagnoses than ADHD, would agree to participate in such a study; but parents eager to streamline their disabled or just different children easily fall into the trap of wanting the child "either cured or dead"."

For the record, while none of the crazy hypotheses criticized in these two posts of mine has been specifically and inequivocally disproven, they have not been confirmed, either. The 2011 review by T. E. Froehlich et al. Update on Environmental Risk Factors for Attention-Deficit/Hyperactivity Disorder discusses a total of 26 (!) environmental factors seriously considered as contributing to ADHD. Most of these factors are ubiquitous, e.g. "Prenatal Caffeine Exposure" and "“Western” Dietary Patterns". Anybody with even rudimentary background and understanding of scientific research will immediately figure out that we are still deep in the woods. I would add that the only useful information in the cited review is the brief mentioning of "ADHD heritability estimates of 60% to 80%".

Double-blind, placebo-controlled trials are rightly considered the gold standard of clinical research. However, I am putting the bar for the gold standard higher. To satisfy my requirements, a study must also:

1) Be done on animals first, unless suitable animal models don't exist, and
2) For life-long conditions, include adult subjects, unless there are very strong reasons to believe that the proposed methods would not work for adults.

These two requirements were not met by the recent study on bumetanide treatment of autism. Explaining their hypothesis in the Introduction chapter, the authors wrote, "GABAergic signals are altered in autism as evidenced by the following: The excitation/inhibition ratio is modified in experimental models..." (5 references cited). However, to my best knowledge, the researchers never tried to test their working hypothesis on these models that so wonderfully provided argumentation to start an experiment on human beings. Also, the authors did not recruit autistic adults for their study. They recruited children aged 3-11. If their idea was to interfere with the full development of the autism spectrum disorder, they should have taken children between 1.5 and 4 years. At the age of 11, autism is considered as fully established as at age 20. Why, then, not recruit adults? I'll tell you why. Because it would be difficult to convince adults to volunteer for such a study, while many parents are happy to put their children through it. In other words, the study was based on the worrying tendency of parents of disabled children to make for their children choices that nobody ever makes for himself.

Are we still in the Dark Ages of scientific ethics?